Dendritic spines are small protrusions that mediate most of the excitatory synaptic transmission in the brain. Their electrical structure and function have long been recognized as essential for understanding how circuits of interconnected neurons encode information and mediate all aspects of behavior. Additionally, numerous reports of spine pathology in neurological and neuropsychiatric disorders including Down syndrome, autism, epilepsy, and schizophrenia highlight their clinical relevance. In spite of their clear biological importance, a complete and consistent description of the electrical structure and function of dendritic spines is not available. To meet this challenge, a novel method of high-sensitivity optical recording was developed to monitor integration of electrical events from individual dendritic spines, miniscule structures less than 1 micrometer in diameter. These measurements, which have never been possible before, pave the way to a new line of research in synaptic physiology of spines. The patch electrode is the gold standard in neurophysiology but is limited in two fundamental ways. First, it only allows measurement near the point of attachment. Second, we cannot attach pipettes to small surfaces, such as spine heads. A novel approach to voltage-imaging solves both these problems. At the conceptual level, a fundamental question that has not been answered is whether the electrical isolation of spine heads by a narrow spine neck provides specific functions which are not available to synapses on dendrites. Several such functions have been postulated, based on modeling and indirect evidence, although they have not been directly or definitively demonstrated: (1) Spines standardize and enhance synaptic activation of voltage-sensitive channels. (2) Changes in the electrical resistance of the spine neck under activity control mediate synaptic plasticity underlying learning and memory formation. (3) Electrical properties of spines promote nonlinear dendritic integration and associated forms of plasticity, thus fundamentally enhancing the computational capabilities of neurons. (4) Spines have the capacity to act as a discrete electrogenic compartments that amplify synaptic potentials by activation of voltage-sensitive channels. It is critical to test these postulates experimentally. If verified, these spine function would define their electrical role and, thus, would represent a potential substrate for pathologica changes and treatments. A novel optical recording will be used in brain slices combined with patch electrode recordings, glutamate uncaging, and computational models to evaluate the above hypotheses by direct recordings of electrical signaling in spines. These measurements will provide fundamental insight about the electrical structure of dendritic spines which is vital or understanding both physiology and pathology of neuronal function.